Post‐COVID‐19‐associated multiorgan complications or “long COVID” with literature review and management strategy discussion: A meta‐analysis

Abstract Objective To investigate the post‐COVID‐19 long‐term complications or long COVID of various organ systems in patients after 3 months of the infection, specifically before the Omicron variant, with comparative literature analysis. Methods A systemic literature search and meta‐analysis were conducted using multiple electronic databases (PubMed, Scopus, Cochrane library) with predefined search terms to identify eligible articles. Eligible studies reported long‐term complications of COVID‐19 infection before the Omicron variant infection. Case reports, case series, observational studies with cross‐sectional or prospective research design, case–control studies, and experimental studies that reported post‐COVID‐19 complications were included. The complications reported after 3 months after the recovery from COVID‐19 infection were included in the study. Results The total number of studies available for analysis was 34. The effect size (ES) for neurological complications was 29% with 95% confidence interval (CI): 19%–39%. ES for psychiatric complications was 24% with 95% CI: 7%–41%. ES was 9% for cardiac outcomes, with a 95% CI of 1%–18%. ES was 22%, 95% CI: 5%–39% for the gastrointestinal outcome. ES for musculoskeletal symptoms was 18% with 95% CI: 9%–28%. ES for pulmonary complications was 28% with 95% CI: 18%–37%. ES for dermatological complications was 25%, with a 95% CI of 23%–26%. ES for endocrine outcomes was 8%, with a 95% CI of 8%–9%. ES size for renal outcomes was 3% with a 95% CI of 1%–7%. At the same time, other miscellaneous uncategorized outcomes had ES of 39% with 95% CI of 21%–57%. Apart from analyzing COVID‐19 systemic complications outcomes, the ES for hospitalization and intensive care unit admissions were found to be 4%, 95% CI: 0%–7%, and 11% with 95% CI: 8%–14%. Conclusion By acquiring the data and statistically analyzing the post‐COVID‐19 complications during the prevalence of most virulent strains, this study has generated a different way of understanding COVID‐19 and its complications for better community health.

generated a different way of understanding COVID-19 and its complications for better community health.

K E Y W O R D S
COVID-19 complications, long COVID, Meta-analysis, Post COVID-19, SARS-CoV-2 sequelae 1 | INTRODUCTION World Health Organization (WHO) has developed a term for post-COVID-19 conditions as "long COVID," defined as coronavirus symptoms that persist or return 3 months after a person becomes ill from infection SARS-CoV-2, commonly known as COVID-19. 1 The most common are headache, fatigue, insomnia, cognitive impairment, posttraumatic stress disorder (PTSD), loss of taste and smell, with heart and kidney problems as well. 1 Since March 11, 2020, COVID-19 has been declared a pandemic that has affected the medical community and economy worldwide. Moreover, till now, the world has been struggling to overcome the disease and its aftermath. Initially, many acute cases of COVID-19 have overwhelmed healthcare resources worldwide, especially the intensive care unit (ICU) departments, and the recovered cases with post-COVID-19 complications have created a challenge for healthcare workers. 2 Currently, long COVID is a situation of concern for a healthy community 3 as estimates of the population that experience post-COVID-19 conditions are roughly 13.3% after 1 month of infection, 2.5% after 3 months or longer while more than 30% after 6 months in hospitalized patient, respectively. 4 Highly infectious and virulent variants of COVID-19, that is, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) and later its variant AY.4.2, sometimes known as delta plus were seen earlier in the course of the pandemic. COVID-19 alpha variant was first reported in Great Britain, a Beta variant in South Africa, and a delta in India in the late 2020s. 5 Later, these variants were also found in other parts of the world due to high infectivity rates. These variants are considered more contagious and virulent, with a greater risk of hospitalization and death. 5 Moreover, this poses a higher risk of increased morbidity and mortality to the community. 5 On the contrary, the COVID-19 Omicron variant is considered relatively less virulent owing to its genetic makeup, mutation, and the increased number of vaccinations across the globe. [6][7][8] mainly affects the respiratory system and commonly presents as fever, cough, and upper respiratory tract infection (URTI). Shortness of breath but other unrelated clinical signs and symptoms such as decreased appetite, anosmia, diarrhea, electrolyte imbalance such as hyponatremia, acute renal failure, fatal thromboembolic complications like stroke, myocardial infarction, pulmonary embolism, and deep venous thrombosis are reported in the literature as well. [9][10][11][12][13][14] COVID-19 has the propensity to cause multiorgan damage through various pathophysiological mechanisms, but the most prominent ones are the cytokine storm and dysregulated immunity. 15

| Quality assessment
Two reviewers independently evaluated study quality using the statistical methodology and categories guided by the Cochrane Collaboration Handbook and PRISMA guidelines ( Figure 1). The protocol is registered at the International Prospective Register of Systematic Reviews (registration number: CRD42021240027).

| Data synthesis and statistical analysis
Results were analyzed descriptively, and meta-analysis was conducted to derive the pooled proportions and effect estimates. We used pooled proportional analysis using STATA software with the command   16 (for more information, visit: www.prisma-statement.org).
The total number of studies available for analysis was 34, and the studies that reported patient outcomes have been included for pooled proportion from a single-arm meta-analysis of proportions of various 21%-57%. Apart from analyzing COVID-19 systemic complications outcomes, the ES for hospitalization and ICU admissions was found to be 4%, CI: 0%-7%, and 11% with CI: 8%-14%. The pooled proportional analysis is mentioned in the forest plot ( Figure 2).

| DISCUSSION
The term "long COVID" by WHO was introduced in late 2021, and the patients who develop symptoms post-COVID-19 are considered "long haulers" 18  SARs COV-2 virus potentially targets several areas of the body where ACE-2 receptors are expressed, such as type-2 pneumocytes, alveolar macrophages in the lungs, enterocytes of intestines, biliary epithelium, nasal epithelium, and hepatocytes. [26][27][28] The damage caused by the virus itself is limited. However, significant cytotoxic and multiorgan damage is caused by dysregulated or hyperimmune response through cytokine release storm that contributes to increased mortality and morbidity. 15 Increased proliferation of the T cells, natural killer cells, macrophages, and most importantly, mast cell activation, has a potential role in releasing various chemokines and activating pro-inflammatory cells, resulting in tissue damage. 15,29 Furthermore, this inflammatory response creates an imbalance in the coagulation cascade and creates a life-threatening risk of thrombosis that can ensue in the form of stroke, myocardial infarction, pulmonary embolism, deep venous thromboembolism, and even sudden cardiac arrest and death. [12][13][14]30 Dysregulated immunity due to COVID-19 is responsible for acute damage in various organ systems and has been shown to play a potential role in post-COVID-19 complications and long-term effects. 31,32 Other possible theories include autoimmunity, endothelial dysfunction, occult viral persistence, and coagulation activation leading to multiorgan damage. 33 Data regarding the long COVID is quite heterogeneous due to different patient analyses and time frames. Therefore the etiology is still unclear and thus creates a dilemma for management. 32  Our study has consolidated the symptoms according to the specific organ/system involved, as mentioned in Table 1

| The dilemma of management for long COVID-19
There is limited data regarding the management of post-COVID symptoms as there is no diagnostic tool or criteria for it, and patients come with various symptoms that may also be related to other

| Strength and limitations
Our study has managed to integrate the organ-specific system-wise post-

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data availability is with the open-access platform of the journal and in the Supporting Information: Material.

ETHICS STATEMENT
Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. It is a meta-analysis with literature review therefore consent is not required for the article.

TRANSPARENCY STATEMENT
The lead author Fateen Ata affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.